LINE-1 (L1) retrotransposons are active elements in the genome capable of mobilization in neuronal precursor cells, resulting in a mosaic brain. Upon mobilization, L1 insertions can alter gene expression, resulting in a genetic heterogenic population of neurons. However, the physiological consequences of somatic L1 retrotransposition are unknown. Our preliminary results showed that L1 retrotransposition levels are increased in a MeCP2 knockout mouse model, indicating that MeCP2 is important for L1 repression during neuronal differentiation in a methylation-independent fashion. Based on this, we postulate that the phenotypic heterogeneity in Rett Syndrome (RTT) could be, at least in part, due to variable neuronal patterns of L1 activity in the brain. The main objective of this proposal is to characterize the molecular complex that represses L1s in undifferentiated neural stem cells and the switch mechanism that unleashes L1 expression during neuronal differentiation. Specific aims are designed to obtain results with cellular models (both rodents and humans) and to attenuate L1 retrotransposition in MeCP2 knockout mice. A battery of behavioral tests will reveal if L1 attenuation could rescue, at least partially, some of neurological defects associated with this mouse model. [unreadable] PUBLIC HEALTH RELEVANCE: The goal of this proposal is to characterize the role of MeCP2 in the control of retrotransposition in nerve cells. For that purpose, we will use several rodent and human cells to monitor the activity of L1 retrotransposons in presence and absence of MeCP2, and the consequences of an attenuated L1 activity to a mouse model of Rett syndrome. The validation of this hypothesis will certainly open new potential possibilities for therapeutic interventions for RTT and other neurological diseases. [unreadable] [unreadable] [unreadable]